Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) and is responsible for long-term morbidity in 250-350,000 people in the United States. Although the precise etiology of MS is unknown, this inflammatory disorder is associated with histologic features suggestive of autoimmune destruction. Myelin-specific immune responses are demonstrable in the peripheral blood and cerebrospinal fluid of MS patients. Autoimmune T cell responses may be directed against various target antigens in the CNS, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG). To understand the pathogenesis of MS, it is crucial to elucidate the fine specificity and exact nature of autoantigen specific responses. Recent powerful methodologies emerging in other areas of Immunology have enabled us to sensitively and specifically characterize human immune responses. We propose to apply these techniques to address important questions regarding the fine specificity, cytokine profile, and the T cell repertoire of responses in MS. In addition, dynamic evolution of these responses will be studied longitudinally in MS patients at different clinical stages of the disease, to study the pathogenic role of "epitope spreading." CNS antigen-specific responses may sometimes be observed in healthy individuals, although these responses are qualitatively different. Prior work suggests that responses from healthy individuals may differ in their costimulatory requirements. Building on these results, we will elucidate the costimulatory requirements of autoreactive T cells and address intrinsic differences in the T cell repertoire in different sets of T cells. The Candidate will be primarily responsible for the formulation of experiments and data analysis and interpretation. His co-Mentors are well-established investigators in distinctive areas of Immunology. The University of Texas Southwestern Medical Center has an excellent environment for basic and clinical research. The Candidate has doctoral experience in Immunology research, specifically in an autoimmune murine model of multiple sclerosis and has recently finished residency and fellowship training in Hematopathology. He will utilize this career development award to further develop new expertise in cutting-edge technology and learn newer approaches in human Immunology, at the same time logically building on his past experience in autoimmunity, in a related area of human disease. This will greatly facilitate his eventual transition into an independent physician-scientist at an academic medical center.